Inducing neurogenesis within a human brain

ABSTRACT

Methods and apparatus for inducing neurogenesis within a human. The invention utilizes an implantable signal generator to deliver high frequency stimulation to deep brain tissue elements. The implanted device delivers treatment therapy to the brain to thereby induce neurogenesis by the human. A sensor may be used to detect various symptoms of nervous system discovery. A microprocessor algorithm may then analyze the output from the sensor to regulate the stimulation and/or drug therapy delivered to the brain.

CROSS-REFERENCES TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 16/544,664 (Attorney Docket No. 41551-704.302), filed Aug. 19,2019, which is a continuation of U.S. patent application Ser. No.14/081,229 (Attorney Docket No. 41551-704.301), filed Nov. 15, 2013, nowU.S. Pat. No. 10,384,053, which is a continuation of U.S. patentapplication Ser. No. 11/303,292 (Attorney Docket No. 41551-704.201, nowU.S. Pat. No. 8,612,006), filed Dec. 16, 2005, which claims priority toU.S. Provisional Application No. 60/636,979 (Attorney Docket No.41551-704.101), filed Dec. 17, 2004, the contents of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to techniques for providing treatmenttherapy to induce neurogenesis within a brain of a human by way ofhigh-frequency brain stimulation and/or drug infusion.

It has generally been believed that loss of neurons in the adult humanbrain—as it occurs in aging humans and in neurological disorders—is anirreversible process. Many major diseases of the human brain involvedeficiencies of select neuronal populations. The inability by the adulthuman brain to generate replacement cells is thought to be a leadingcause for the irreversible and progressive nature of severalneurological diseases and is responsible for persistent and ongoingimpairment. In most regions of the human brain, the generation ofneurons is generally confined to a discrete developmental period. Afterthis developmental period, it believed that no further generation ofbrain cells occurs in the living human brain.

Exceptions to this general rule exist in specific regions of the adultmammalian brain. The dentate gyms of the hippocampus and thesubventricular zone have been shown to generate new neurons well intothe postnatal and adult period. For example, in the rodent brain,granule neurons may be generated throughout life from a population ofcontinuously dividing progenitor cells residing in the subgranular zoneof the dentate gyms. It is likely that the human brain may also enjoythese regenerative features.

Attempts have been made to learn more about possible neurogenesis in theadult human brain. For example, scientists have dissected human braintissue from postmortem patients to achieve neurogenesis. Unfortunately,however, the genesis of new neurons in situ in the living adult humanbrain and methods to enhance, control or modulate this process have notyet been demonstrated. Accordingly, attempts have been made to preventor slow down neurodegeneration of the human brain. For example, U.S.Pat. No. 5,683,422 discloses techniques for treating neurodegenerativedisorders by electrical brain stimulation. Similarly, U.S. Pat. No.5,707,396 describes methods of arresting degeneration of the neurons byhigh frequency stimulation.

It is therefore desirable to provide a technique for inducingneurogenesis (namely, the producing of new or replacement neurons)within a living brain of an adult human.

BRIEF SUMMARY OF THE INVENTION

An embodiment of the invention uses high frequency electricalstimulation of deep brain elements of a human to induce neurogenesis.The treatment is carried out by an implantable signal generator and atleast one implantable electrode having a proximal end coupled to thesignal generator and having a stimulation portion for electricallyaffecting deep brain tissue elements of a human. Alternatively, thetreatment may be carried out by an implantable pump and at least onecatheter having a proximal end coupled to the pump and having adischarge portion for infusing therapeutic dosages of the one or moredrugs into a predetermined infusion site in deep brain elements. Byusing the foregoing techniques, neurogenesis within a human can besignificantly improved. In other embodiments of the invention, druginfusion may be used as treatment therapy instead of or in addition tothe electrical stimulation.

In another embodiment of the invention, a sensor is used in combinationwith the signal generator and stimulating electrodes to induceneurgenesis. Control means responsive to the sensor may thereby regulatethe signal generator and/or pump so that the neurological disorder istreated.

By using the foregoing techniques, neurodegenerative and cognitivedisorders can be controlled or treated to a degree unattainable by priorart methods or apparatus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic illustration of an electrode implanted in abrain according to an embodiment of the present invention and a signalgenerator coupled to the electrode.

FIGS. 2 and 2A are diagrammatic illustrations of a catheter implanted ina brain according to an embodiment of the present invention.

FIG. 3 is a schematic block diagram of a microprocessor and relatedcircuitry of an implantable medical device for use with the presentinvention.

FIG. 4A is a diagram depicting the anterior thalamic nuclei complex andFIG. 4B is a diagram depicting the dentate gyms.

DETAILED DESCRIPTION OF THE INVENTION

The invention discloses techniques for delivering treatment therapy todeep brain elements of a human brain to induce neurogenesis. Theapplicants have discovered that neurogenesis can be induced throughdelivery of treatment therapy such as high frequency stimulation to deepbrain elements. In one experiment, high frequency stimulation was usedof the anterior thalamic nuclei to find that this surgical approachenhanced neurogenesis in rats. Accordingly, the invention incorporateselectrical stimulation and/or drug infusion techniques to directly orindirectly influence tissue elements within the brain. One or moreelectrodes and/or catheters are implanted in the brain so that thestimulation or infusion portions lie within or in communication withpredetermined portions of the brain. The electrical stimulation or drugtherapy influences the deep brain elements to achieve the desiredresult.

These techniques of the present invention are suitable for use withinany implantable medical device. In an embodiment, the present inventionis implemented within an implantable neurostimulator system, however,those skilled in the art will appreciate that the present invention maybe implemented generally within any implantable medical device systemincluding, but not limited to, implantable drug delivery systems,implantable systems providing stimulation and drug delivery.

The present invention may be utilized to treat, for example, any numberof conditions that exhibit neuronal loss including, but not limited to,depression, epilepsy, post cranial irradiation, steroid inducedimpairment in neurogenesis, stress disorders, cognitive disorders,Alzheimer's disease, mild cognitive impairment (MCI), and otherneurodegenerative diseases. Such other neurodegenerative diseasesinclude Amyotrophic lateral sclerosis (ALS), Huntingtons,Spinocerebellar ataxias (SCA's).

The targeted treatment site are deep brain elements of the human brainand include, for example, the anterior thalamic nuclei complex (FIG.4(a)), the periventricular zone, the Papez circuit, and the cerebellum.The Papez circuit is generally a neuronal circuit in the limbic system,consisting of the hippocampus, fornix, mammillary body, anteriorthalamic nuclei, and cingulate gyms. Stimulation or drug therapy alongthe Papez circuit may lead to neurogenesis in the hippocampus. When theperiventricular zone is influenced in accordance with the presentinvention, new neurons may migrate to the striatum, cortex, or thesubstantia nigra, and brainstem and therefore lead to the repopulationof neurons in such areas. The cerebellum is another brain location whereincreasing neurogenesis may be therapeutically desirable. In particular,the foregoing techniques may be used to reactivate neurogenesis later inlife by application of electrical stimulation in either the cerebellumor cerebellar afferent or efferents. In each instance and for eachtarget, the application of neurotrophic factors could also be used toenhance neurogenesis for therapeutic goals.

Thus, the site of stimulation may be chosen based on the neuralstructures that are affected by neuronal loss and which ones wouldbenefit from enhanced neurogenesis. For example, targeting thehippocampal neuronal loss may be utilized to treat depression, epilepsy,post cranial irradiation, steroid induced impairment in neurogenesis,stress disorders, cognitive disorders and Alzheimer's disease. Targetingthe cortical, striatal, substantia nigra, brainstem and cerebellar lossmay be utilized to treat Huntington's Disease, Alzheimers, multiplesystem atrophy, Parkinson's disease, post-irradiation disorders,paraneoplastic disorders and the Spinocerebellar ataxias. The techniquesof the present invention may also be applicable to treat neuronal lossthat occurs as a consequence of congenital disorders, stroke, anoxia,hypoxia, hypoglycemia, metabolic disorders, head injury, drug andalcohol toxicity, nutritional deficiencies, auto-immune, infectious andinflammatory processes.

Referring to FIG. 1 , an implantable neurostimulator device 16 made inaccordance with an embodiment may be implanted below the skin of apatient. A lead 522A is positioned to stimulate a specific site 525 in abrain (B). Device 16 may take the form of a modified signal generatorModel 7424 manufactured by Medtronic, Inc. under the trademark Itrel IIwhich is incorporated by reference. Lead 522A may take the form of anyof the leads sold with the Model 7424 such as Model 3387, forstimulating the brain, and is coupled to device 16 by a conventionalconductor 522. One or more external programmers (not shown) may beutilized to program and/or communicate bi-directionally with theimplanted device 16.

As shown, the distal end of lead 522A terminates in four stimulationelectrodes implanted into a portion of the brain by conventionalstereotactic surgical techniques. Each of the four electrodes isindividually connected to device 16 through lead 522A and conductor 522.Lead 522A is surgically implanted through a hole in the skull 123 andconductor 522 is implanted between the skull and the scalp 125 as shownin FIG. 1 . Conductor 522 is joined to implanted device 16 in the mannershown. Referring to FIG. 2A, device 16 is implanted in a human body 120in the location shown. Body 120 includes arms 122 and 123.Alternatively, device 16 may be implanted in the abdomen. Conductor 522may be divided into twin leads 522A and 522B that are implanted into thebrain bilaterally as shown. Alternatively, lead 522B may be suppliedwith stimulating pulses from a separate conductor and signal generator.Leads 522A and 522B could be 1) two electrodes in two separate nucleithat potentiate each others effects or 2) nuclei with opposite effectswith the stimulation being used to fine tune the response throughopposing forces. It will be appreciated, however, that any number ofelectrodes may be implanted within the brain in accordance with theinvention. Additionally, one or more secondary electrodes may beimplanted so that a secondary stimulation portion lies in communicationwith another predetermined portion of a brain. Moreover, as will bediscussed below, one or more catheters, coupled to a pump, may beimplanted so that a secondary stimulation portion lies in communicationwith the tissue elements of the brain.

The device 16 may be operated to deliver stimulation to deep braintissue elements to thereby induce neurogenesis within the human brain.The particular stimulation delivered may be performed by selectingamplitude, width and frequency of stimulation by the electrode. Thepossible stimulations include between 50 Hertz and 1000 Hertz forfrequency, between 0.1 Volts and 10.0 Volts for pulse amplitude, andbetween 30 μSeconds and 450 μSeconds for pulse width.

The system may be utilized in monopolar, bipolar, or multipolarconfigurations, in an either continuous or cyclical mode, and in eitheran open loop or closed loop mode. In an embodiment, bipolar stimulationof the hypothalamus may be utilized with the following stimulationparameters: 130 Hz, 80 microsec pulse width and 2.5 Volts. In anotherembodiment, monopolar stimulation of the hypothalamus may be utilizedwith the following stimulation parameters: 50 Hz to 1000 Hz, 30microseconds pulse width to 450 microseconds and 0.1 to 10 Volts.

Referring to FIG. 2 , in another embodiment, the system or device of thepresent invention may utilize drug delivery as the form of treatmenttherapy. A pump 10 may be implanted below the skin of a patient. Thepump 10 has a port 14 into which a hypodermic needle can be insertedthrough the skin to inject a quantity of a liquid agent, such as amedication or drug. The liquid agent is delivered from pump 10 through acatheter port 20 into a catheter 422. Catheter 422 is positioned todeliver the agent to specific infusion sites in a brain (B). Pump 10 maytake the form of any number of known implantable pumps including forexample that which is disclosed in U.S. Pat. No. 4,692,147.

The distal end of catheter 422 terminates in a cylindrical hollow tube422A having a distal end 425 implanted, by conventional stereotacticsurgical techniques, into a portion of the brain to affect tissue withinthe human brain. Tube 422A is surgically implanted through a hole in theskull and catheter 422 is implanted between the skull and the scalp asshown in FIG. 2 . Catheter 422 is joined to pump 10 in the manner shown.Pump 10 is implanted in a human body in a subcutaneous pocket located inthe chest below the clavicle. Alternatively, pump 10 may be implanted inthe abdomen.

Catheter 422 may be divided into twin tubes 422A and 422B (not shown)that are implanted into the brain bilaterally. Alternatively, tube 422B(not shown) implanted on the other side of the brain may be suppliedwith drugs from a separate catheter and pump.

The pump 10 may be programmed to deliver drug according to a particulardosage and/or time interval. For example, the pump may delivery drugtherapy over a first period when the dose is higher to induce a highlevel of neurogenesis followed by a longer period of ongoing delivery tomaintain neurogenesis and secondary trophic effects like axonalsprouting and synaptogenesis. Any number of neurotrophins or drugs thatstimulate neurons may be administered including, but not limited to,NGF, BDNF, NT-3, FGF, EGF, GDNF, Neurteurin, Artemin, Persephin.

Alternatively, a combination of treatment therapies may be delivered toprovide influencing of various neuronal types. For example, it may bedesirable to concurrently influence, via drug and/or electricalstimulation, the neurons in the hippocampus and other portions of thebrain to achieve an improved result. Such a device to utilize both formsof treatment therapy may be that which is disclosed, for example, inU.S. Pat. No. 5,782,798. In addition to affecting the deep brain, it maybe desirable to affect concurrently other portions of the brain.

Referring to FIG. 3 , the overall components of the implanted device 16are shown (similar components may also be found for pump 10). Thestimulus pulse frequency is controlled by programming a value to aprogrammable frequency generator 208 using bus 202. The programmablefrequency generator provides an interrupt signal to microprocessor 200through an interrupt line 210 when each stimulus pulse is to begenerated. The frequency generator may be implemented by model CDP1878sold by Harris Corporation. The amplitude for each stimulus pulse isprogrammed to a digital to analog converter 218 using bus 202. Theanalog output is conveyed through a conductor 220 to an output drivercircuit 224 to control stimulus amplitude.

Microprocessor 200 also programs a pulse width control module 214 usingbus 202. The pulse width control provides an enabling pulse of durationequal to the pulse width via a conductor 216. Pulses with the selectedcharacteristics are then delivered from device 16 through cable 522 andlead 522A to the desired regions of the brain.

At the time the stimulation device 16 is implanted, the clinicianprograms certain key parameters into the memory of the implanted devicevia telemetry. These parameters may be updated subsequently as needed.

The embodiments of the present invention shown above are open-loopsystems. The microcomputer algorithm programmed by the clinician setsthe stimulation parameters of signal generator 16. This algorithm maychange the parameter values over time but does so independent of anychanges in symptoms the patient may be experiencing. Alternatively, aclosed-loop system discussed below which incorporate a sensor 130 toprovide feedback could be used to provide enhanced results. Sensor 130can be used with a closed loop feedback system in order to automaticallydetermine the level of electrical stimulation necessary to achieve thedesired level of neurogenesis. In a closed-loop embodiment,microprocessor 200 executes a control algorithm in order to providestimulation with closed loop feedback control. Such an algorithm mayanalyze a sensed signal and deliver the electrical or chemical treatmenttherapy based on the sensed signal falling within or outsidepredetermined values or windows, for example, for BDNF and otherneurotrophins (e.g., NGF, CNTF, FGF EGF, NT-3) and corticosteroids.

The control algorithm may be operable on-line or in real time bydetecting an electophysiological or chemical signal or off line bymeasuring a predetermined clinical benefit. Alternatively, the therapycould be guided by the goal of repopulating neurons up to a certainlevel. Such an increase in of neuronal number could be assessed usingthe techniques described below.

For example, the sensor may generate a sensor signal related to theextent of neuronal loss. In an embodiment, the extent of electricalactivity or the levels of a neurochemical may be measured that areindicative of neuronal loss. For example magnetic resonance spectroscopymay be used to sense the N-acetylaspartate (NAA) to creatine (Cr) ratio(NAA/Cr) as an indicator of neuronal loss. Alternatively, the neuronalloss may be estimated by measuring the volume of the neural structure ofinterest, which may be achieved by Magnetic Resonance Imagingvollumetry. Any other techniques may also be used to sense the extent ofneuronal loss including, for example, MR volumetry, DWI, magnetizationtransfer MR imaging, and 1H MRS and PET).

As another example, the sensing may provide an indication of a cognitivedisorder. Thus, sensor 130 may be placed in the dentate gyms (FIG. 4(b))to confirm that stimulation at the anterior thalamic nuclei affectsneuronal activity of the hippocampus. U.S. Pat. No. 6,227,203 providesexamples of various types of sensors that may be used to detect asymptom or a condition of a cognitive disorder and responsively generatea neurological signal. In an embodiment, a neurochemical characteristicof the cognitive function may be sensed, additionally or alternatively.For example, sensing of local levels of neurotransmitters (glutamate,GABA, Aspartate), local pH or ion concentration, lactate levels, localcerebral blood flow, glucose utilization or oxygen extraction may alsobe used as the input component of a closed loop system. Thesemeasurements could be taken at rest or in response to a specific memoryor cognitive task or in response to a specific sensory or motorstimulus. In another embodiment, an electro-physiological characteristicof the cognitive function may be sensed, for example, the frequency andpattern of discharge of individual neurons or the amplitude of a localelectric field potential. The information contained within the neuronalfiring spike train, including spike amplitude, frequency of actionpotentials, signal to noise ratio, the spatial and temporal features andthe pattern of neuronal firing, oscillation behavior and inter-neuronalcorrelated activity could be used to deliver therapies on a contingencybasis in a closed loop system. Moreover, treatment therapy delivered maybe immediate or delayed, diurnal, constant or intermittent depending oncontingencies as defined by the closed loop system.

In one embodiment, the system may provide continuous closed-loopfeedback control. In another embodiment, the system may be switchablebetween open-loop and closed-loop by operator control.

Referring back to FIG. 3 , the system may optionally utilize closed-loopfeedback control having an analog to digital converter 206 coupled tosensor 130. Output of the A-to-D converter 206 is connected tomicroprocessor 200 through peripheral bus 202 including address, dataand control lines. Microprocessor 200 processes sensor data in differentways depending on the type of transducer in use and regulates delivery,via a control algorithm, of electrical stimulation and/or drug deliverybased on the sensed signal. For example, when the signal on sensor 130exceeds a level programmed by the clinician and stored in a memory 204,increasing amounts of treatment therapy may be applied through an outputdriver 224. In the case of electrical stimulation, a parameter of thestimulation may be adjusted such as amplitude, pulse width and/orfrequency.

In another aspect of the invention, treatment therapy may be utilized toalso improve cognitive function. Techniques for improving cognitivefunction through treatment therapy are disclosed in a co-pending patentapplication entitled “Improving Cognitive Function Within A HumanBrain,” filed concurrent with the instant application and incorporatedherein by reference in its entirety.

Thus, embodiments of INDUCING NEUROGENESIS WITHIN A HUMAN BRAIN aredisclosed. One skilled in the art will appreciate that the presentinvention can be practiced with embodiments other than those disclosed.The disclosed embodiments are presented for purposes of illustration andnot limitation, and the present invention is limited only by the claimsthat follow.

What is claimed is:
 1. A method for inducing neurogenesis within a humanby means of an implantable signal generator and a lead having a proximalend coupled to the signal generator and a distal portion having at leastone electrode, the method comprising: (A) implanting at least oneelectrode so that the stimulation portion lies at least in communicationwith deep brain tissue elements of a human brain; (B) coupling theproximal end of the implanted electrode to the signal generator; and (C)operating the signal generator to deliver high frequency stimulation tothe deep brain tissue elements to thereby induce neurogenesis within thebrain.